Tight nuclear tethering of cGAS is essential for preventing autoreactivity
Open accessAbstract
cGAS is an intracellular innate immune sensor that detects double-stranded DNA. The presence of billions of base pairs of genomic DNA in all nucleated cells raises the question of how cGAS is not constitutively activated. A widely accepted explanation for this is the sequestration of cGAS in the cytosol, which is thought to prevent cGAS from accessing nuclear DNA. Here, we demonstrate that endogenous cGAS is predominantly a nuclear protein, regardless of cell cycle phase or cGAS activation status. We show that nuclear cGAS is tethered tightly by a salt-resistant interaction. This tight tethering is independent of the domains required for cGAS activation, and it requires intact nuclear chromatin. We identify the evolutionarily conserved tethering surface on cGAS and we show that mutation of single amino acids within this surface renders cGAS massively and constitutively active against self-DNA. Thus, tight nuclear tethering maintains the resting state of cGAS and prevents autoreactivity.
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cGAS is suppressed by binding to nucleosomes and disruption of nucleosome regulation enables robust DNA-dependent activation of cGAS.
“Previously, we and others showed that cGAS is suppressed by binding to nucleosomes and that disruption of nucleosome regulation enables robust DNA-dependent activation of cGAS32–37 (Fig. 4a).”
From cGAS–STING drives ageing-related inflammation and neurodegeneration (2023) · cites this paper as [37]
The Results section, “Identification of the evolutionarily conserved cGAS tethering surface,” shows that disrupting nuclear tethering produces strong, DNA-dependent activation of cGAS. But the Discussion says the identity of the chromatin tether remains unclear and does not establish that binding to nucleosomes is what suppresses cGAS; it describes nucleosome-binding evidence from an in vitro study as of uncertain relevance to its findings in cells. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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Cites
Improved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239 · see citing works
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
Sun, L., Wu, J., Du, F., Chen, X., & Chen, Z. J. (2013) · Science · doi:10.1126/science.1232458 · Cited by 4,996 · see citing works
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
Ishikawa, H., Ma, Z., & Barber, G. N. (2009) · Nature · doi:10.1038/nature08476 · Cited by 2,759 · see citing works
Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA
Wu, J., Sun, L., Chen, X., Du, F., Shi, H., Chen, C., & Chen, Z. J. (2012) · Science · doi:10.1126/science.1229963 · Cited by 2,574 · see citing works
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation
Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y.-T., Grishin, N. V., et al. (2015) · Science · doi:10.1126/science.aaa2630 · Cited by 1,927 · see citing works
cGAS surveillance of micronuclei links genome instability to innate immunity
Mackenzie, K. J., Carroll, P., Martin, C.-A., Murina, O., Fluteau, A., Simpson, D. J., Olova, N., Sutcliffe, H., Rainger, J. K., Leitch, A., et al. (2017) · Nature · doi:10.1038/nature23449 · Cited by 1,752 · see citing works
Mitotic progression following DNA damage enables pattern recognition within micronuclei
Harding, S. M., Benci, J. L., Irianto, J., Discher, D. E., Minn, A. J., & Greenberg, R. A. (2017) · Nature · doi:10.1038/nature23470 · Cited by 1,508 · see citing works
Cytoplasmic chromatin triggers inflammation in senescence and cancer
Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., et al. (2017) · Nature · doi:10.1038/nature24050 · Cited by 1,335 · see citing works
The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer
Li, T., & Chen, Z. J. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180139 · Cited by 1,293 · see citing works
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
Glück, S., Guey, B., Gulen, M. F., Wolter, K., Kang, T.-W., Schmacke, N. A., Bridgeman, A., Rehwinkel, J., Zender, L., & Ablasser, A. (2017) · Nature Cell Biology · doi:10.1038/ncb3586 · Cited by 1,196 · see citing works
DNA-induced liquid phase condensation of cGAS activates innate immune signaling
Du, M., & Chen, Z. J. (2018) · Science · doi:10.1126/science.aat1022 · Cited by 1,068 · see citing works
Extraction, purification and analysis of histones
Shechter, D., Dormann, H. L., Allis, C. D., & Hake, S. B. (2007) · Nature Protocols · doi:10.1038/nprot.2007.202 · Cited by 1,054 · see citing works
cGAS is essential for cellular senescence
Yang, H., Wang, H., Ren, J., Chen, Q., & Chen, Z. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705499114 · Cited by 1,009 · see citing works
Recognition of Cytosolic DNA Activates an IRF3-Dependent Innate Immune Response
Stetson, D. B., & Medzhitov, R. M. (2006) · Immunity · doi:10.1016/j.immuni.2005.12.003 · Cited by 1,003 · see citing works
Self-citationCyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses
Gao, D., Wu, J., Wu, Y.-T., Du, F., Aroh, C., Yan, N., Sun, L., & Chen, Z. J. (2013) · Science · doi:10.1126/science.1240933 · Cited by 986 · see citing works
Structural mechanism of cytosolic DNA sensing by cGAS
Çivril, F., Deimling, T., Mann, C. C. D. O., Ablasser, A., Moldt, M., Witte, G., Hornung, V., & Hopfner, K. (2013) · Nature · doi:10.1038/nature12305 · Cited by 888 · see citing works
Goubau, D., Deddouche, S., & Sousa, C. R. E. (2013) · Immunity · doi:10.1016/j.immuni.2013.05.007 · Cited by 847 · see citing works
Chromothripsis and Kataegis Induced by Telomere Crisis
Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J., & de Lange, T. (2015) · Cell · doi:10.1016/j.cell.2015.11.054 · Cited by 675 · see citing works
Cyclic GMP-AMP Synthase Is Activated by Double-Stranded DNA-Induced Oligomerization
Li, X., Shu, C., Yi, G., Chaton, C. T., Shelton, C. L., Diao, J., Zuo, X., Kao, C. C., Herr, A. B., & Li, P. (2013) · Immunity · doi:10.1016/j.immuni.2013.10.019 · Cited by 656 · see citing works
Nuclear cGAS suppresses DNA repair and promotes tumorigenesis
Liu, H., Zhang, H., Wu, X., Ma, D., Wu, J., Wang, L., Jiang, Y., Fei, Y., Zhu, C., Tan, R., et al. (2018) · Nature · doi:10.1038/s41586-018-0629-6 · Cited by 651 · see citing works
Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6
Toogood, P. L., Harvey, P. J., Repine, J. T., Sheehan, D. J., VanderWel, S. N., Zhou, H., Keller, P. R., McNamara, D. J., Sherry, D., Zhu, T., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm049354h · Cited by 513 · see citing works
cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders
Andreeva, L., Hiller, B., Kostrewa, D., Lässig, C., de Oliveira Mann, C. C., Jan Drexler, D., Maiser, A., Gaidt, M., Leonhardt, H., Hornung, V., et al. (2017) · Nature · doi:10.1038/nature23890 · Cited by 511 · see citing works
HIV-1 evades innate immune recognition through specific cofactor recruitment
Rasaiyaah, J., Tan, C. P., Fletcher, A. J., Price, A. J., Blondeau, C., Hilditch, L., Jacques, D. A., Selwood, D. L., James, L. C., Noursadeghi, M., et al. (2013) · Nature · doi:10.1038/nature12769 · Cited by 465 · see citing works
DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway
Lau, L., Gray, E. E., Brunette, R. L., & Stetson, D. B. (2015) · Science · doi:10.1126/science.aab3291 · Cited by 450 · see citing works
Self-citationThe Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death
Zierhut, C., Yamaguchi, N., Paredes, M. C. G., Luo, J., Carroll, T., & Funabiki, H. (2019) · Cell · doi:10.1016/j.cell.2019.05.035 · Cited by 403 · see citing works
Lahaye, X., Satoh, T., Gentili, M., Cerboni, S., Conrad, C., Hurbain, I., El Marjou, A., Lacabaratz, C., Lelièvre, J.-D., & Manel, N. (2013) · Immunity · doi:10.1016/j.immuni.2013.11.002 · Cited by 390 · see citing works
Gray, E. E., Treuting, P. M., Woodward, J. J., & Stetson, D. B. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500969 · Cited by 384 · see citing works
Self-citationStructure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance
Zhou, W., Whiteley, A. T., Mann, C. C. D. O., Morehouse, B. R., Nowak, R. P., Fischer, E. S., Gray, N. S., Mekalanos, J. J., & Kranzusch, P. J. (2018) · Cell · doi:10.1016/j.cell.2018.06.026 · Cited by 380 · see citing works
Studies on synchronous division of tissue culture cells initiated by excess thymidine
Bootsma, D., Budke, L., & Vos, O. (1964) · Experimental Cell Research · doi:10.1016/s0014-4827(64)81035-1 · Cited by 342 · see citing works
Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses
Ma, Z., Jacobs, S. R., West, J. A., Stopford, C. M., Zhang, Z., Davis, Z. H., Barber, G. N., Glaunsinger, B. A., Dittmer, D. P., & Damania, B. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1503831112 · Cited by 311 · see citing works
A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-Mediated Exhaustion
Xia, P., Wang, S., Ye, B., Du, Y., Li, C., Xiong, Z., Qu, Y., & Fan, Z. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.016 · Cited by 279 · see citing works
Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein
Wu, J., Li, W., Shao, Y., Avey, D. R., Fu, B., Gillen, J., Hand, T. H., Ma, S., Liu, X., Miley, W., et al. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.07.015 · Cited by 278 · see citing works
Barnett, K. C., Coronas-Serna, J. M., Zhou, W., Ernandes, M. J., Cao, A., Kranzusch, P. J., & Kagan, J. C. (2019) · Cell · doi:10.1016/j.cell.2019.01.049 · Cited by 268 · see citing works
cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection
Orzalli, M. H., Broekema, N. M., Diner, B. A., Hancks, D. C., Elde, N. C., Cristea, I. M., & Knipe, D. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1424637112 · Cited by 264 · see citing works
Jiang, H., Xue, X., Panda, S., Kawale, A. S., Hooy, R. M., Liang, F., Sohn, J., Sung, P., & Gekara, N. O. (2019) · The EMBO Journal · doi:10.15252/embj.2019102718 · Cited by 263 · see citing works
Gentili, M., Lahaye, X., Nadalin, F., Nader, G. P. F., Lombardi, E. P., Hervé, S., Silva, N. S. D., Rookhuizen, D. C., Zueva, E., Goudot, C., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.105 · Cited by 248 · see citing works
NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation
Lahaye, X., Gentili, M., Silvin, A., Conrad, C., Picard, L., Jouve, M. J., Zueva, E., Maurin, M., Nadalin, F., Knott, G. J., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.062 · Cited by 227 · see citing works
Intracellular Nucleic Acid Detection in Autoimmunity
Crowl, J. T., Gray, E. E., Pestal, K., Volkman, H. E., & Stetson, D. B. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052331 · Cited by 217 · see citing works
Self-citationAbsence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy
Bartsch, K., Knittler, K., Borowski, C., Rudnik, S., Damme, M., Aden, K., Spehlmann, M. E., Frey, N., Saftig, P., Chalaris, A., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx283 · Cited by 196 · see citing works
The AIM2-like Receptors Are Dispensable for the Interferon Response to Intracellular DNA
Gray, E. E., Winship, D., Snyder, J. M., Child, S. J., Geballe, A. P., & Stetson, D. B. (2016) · Immunity · doi:10.1016/j.immuni.2016.06.015 · Cited by 183 · see citing works
Self-citationStructural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling
Ibsen, M. S., Gad, H. H., Andersen, L. L., Hornung, V., Julkunen, I., Sarkar, S. N., & Hartmann, R. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv389 · Cited by 76 · see citing works
Gentili, M., Lahaye, X., Nadalin, F., Nader, G. P. F., Lombardi, E. P., Hervé, S., Silva, N. S. D., Rookhuizen, D. C., Zueva, E., Goudot, C., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.049 · Cited by 64 · see citing works
Luo, Y., Tucker, S. C., & Casadevall, A. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.11.7226 · Cited by 46 · see citing works
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Decout, A., Katz, J. D., Venkatraman, S., & Ablasser, A. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00524-z · Cited by 2,309 · see citing works
Molecular mechanisms and cellular functions of cGAS–STING signalling
Hopfner, K.-P., & Hornung, V. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0244-x · Cited by 2,052 · see citing works
cGAS–STING drives ageing-related inflammation and neurodegeneration
Gulen, M. F., Samson, N., Keller, A., Schwabenland, M., Liu, C., Glück, S., Thacker, V. V., Favre, L., Mangeat, B., Kroese, L. J., et al. (2023) · Nature · doi:10.1038/s41586-023-06373-1 · Cited by 1,074 · see citing works
Mitochondrial DNA in inflammation and immunity
Riley, J. S., & Tait, S. W. G. (2020) · EMBO Reports · doi:10.15252/embr.201949799 · Cited by 876 · see citing works
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Zhang, X., Bai, X., & Chen, Z. J. (2020) · Immunity · doi:10.1016/j.immuni.2020.05.013 · Cited by 845 · see citing works
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Garland, K. M., Sheehy, T. L., & Wilson, J. T. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00750 · Cited by 368 · see citing works
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Self-citationOduro, P. K., Zheng, X., Wei, J., Yang, Y., Wang, Y., Zhang, H., Liu, E., Gao, X., Du, M., & Wang, Q. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.05.011 · Cited by 349 · see citing works
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Lei, Y., VanPortfliet, J. J., Chen, Y., Bryant, J. D., Li, Y., Fails, D., Torres-Odio, S., Ragan, K. B., Deng, J., Mohan, A., et al. (2023) · Cell · doi:10.1016/j.cell.2023.05.039 · Cited by 292 · see citing works
Cytoplasmic DNA: sources, sensing, and role in aging and disease
Miller, K. N., Victorelli, S. G., Salmonowicz, H., Dasgupta, N., Liu, T., Passos, J. F., & Adams, P. D. (2021) · Cell · doi:10.1016/j.cell.2021.09.034 · Cited by 288 · see citing works
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Self-citationPan, J., 宁波大学农产品质量安全危害因子与风险防控国家重点实验室, 浙. 宁. 3., Fei, C.-J., Hu, Y., Wu, X., Nie, L., Chen, J., 宁波大学梅山校区海洋学院生物化学与分子生物学实验室, 浙. 宁. 3., & 浙江省海洋生物工程重点实验室, 浙. 宁. 3. (2023) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2022.464 · Cited by 129 · see citing works
Fang, L., Hao, Y., Yu, H., Gu, X., Peng, Q., Zhuo, H., Li, Y., Liu, Z., Wang, J., Chen, Y., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.05.005 · Cited by 126 · see citing works
RetractedStructural basis for nucleosome-mediated inhibition of cGAS activity
Cao, D., Han, X., Fan, X., Xu, R.-M., & Zhang, X. (2020) · Cell Research · doi:10.1038/s41422-020-00422-4 · Cited by 126 · see citing works
Biochemistry, Cell Biology, and Pathophysiology of the Innate Immune cGAS–cGAMP–STING Pathway
Ritchie, C., Carozza, J. A., & Li, L. (2022) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-040320-101629 · Cited by 121 · see citing works
Significance of the cGAS-STING Pathway in Health and Disease
Zhou, J., Zhuang, Z., Li, J., & Feng, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713316 · Cited by 121 · see citing works
Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production
Weinreb, J. T., Ghazale, N., Pradhan, K., Gupta, V., Potts, K. S., Tricomi, B. J., Daniels, N. J., Padgett, R. A., de Oliveira, S., Verma, A. K., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.02.006 · Cited by 120 · see citing works
STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?
Smith, J. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.611347 · Cited by 114 · see citing works
Sun, Z., & Hornung, V. (2022) · Current Biology · doi:10.1016/j.cub.2022.05.027 · Cited by 106 · see citing works
A Nuclear Export Signal Is Required for cGAS to Sense Cytosolic DNA
Sun, H., Huang, Y., Mei, S., Xu, F., Liu, X., Zhao, F., Yin, L., Zhang, D., Wei, L., Wu, C., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108586 · Cited by 105 · see citing works
cGAS‒STING signaling and function in metabolism and kidney diseases
Bai, J., & Liu, F. (2021) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjab066 · Cited by 99 · see citing works
Quan, S., Fu, X., Cai, H., Ren, Z., Xu, Y., & Jia, L. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00815-2 · Cited by 107 · see citing works
Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity
Zahid, A., Ismail, H., Li, B., & Jin, T. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.613039 · Cited by 100 · see citing works
STING-Mediated Lung Inflammation and Beyond
Frémond, M., & Crow, Y. J. (2021) · Journal of Clinical Immunology · doi:10.1007/s10875-021-00974-z · Cited by 95 · see citing works
Translation stress and collided ribosomes are co-activators of cGAS
Wan, L., Juszkiewicz, S., Blears, D., Bajpe, P. K., Han, Z., Faull, P. A., Mitter, R., Stewart, A., Snijders, A. P., Hegde, R. S., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.05.018 · Cited by 92 · see citing works
Sensing of transposable elements by the antiviral innate immune system
Gázquez-Gutiérrez, A., Witteveldt, J., Heras, S. R., & Macías, S. (2021) · RNA · doi:10.1261/rna.078721.121 · Cited by 92 · see citing works
Regulation and Consequences of cGAS Activation by Self-DNA
Zierhut, C., & Funabiki, H. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.05.006 · Cited by 89 · see citing works
The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA
Kumar, V. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.624597 · Cited by 93 · see citing works
Takaki, T., Millar, R., Hiley, C. T., & Boulton, S. J. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.04.017 · Cited by 95 · see citing works
Nucleic Acid Sensors as Therapeutic Targets for Human Disease
McWhirter, S. M., & Jefferies, C. A. (2020) · Immunity · doi:10.1016/j.immuni.2020.04.004 · Cited by 90 · see citing works
CGAS is a micronucleophagy receptor for the clearance of micronuclei
Zhao, M., Wang, F., Wu, J., Cheng, Y., Cao, Y., Wu, X., Ma, M., Tang, F., Liu, Z., Liu, H., et al. (2021) · Autophagy · doi:10.1080/15548627.2021.1899440 · Cited by 89 · see citing works
Mitotic disassembly and reassembly of nuclear pore complexes
Kutay, U., Jühlen, R., & Antonin, W. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.06.011 · Cited by 84 · see citing works
Banerjee, D., Langberg, K. A., Abbas, S., Odermatt, E., Yerramothu, P., Volaric, M. P., Reidenbach, M. A., Krentz, K. J., Rubinstein, C. D., Brautigan, D. L., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26240-9 · Cited by 84 · see citing works
cGAS‐STING pathway agonists are promising vaccine adjuvants
Tian, X., Ai, J., Tian, X., & Wei, X. (2024) · Medicinal Research Reviews · doi:10.1002/med.22016 · Cited by 83 · see citing works
cGAS restricts colon cancer development by protecting intestinal barrier integrity
Hu, S., Fang, Y., Chen, X., Cheng, T., Zhao, M., Du, M., Li, T., Li, M., Zeng, Z., Wei, Y., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2105747118 · Cited by 83 · see citing works
DDX41 is required for cGAS-STING activation against DNA virus infection
Singh, R. S., Vidhyasagar, V., Yang, S., Arna, A. B., Yadav, M., Aggarwal, A., Aguilera, A. N., Shinriki, S., Bhanumathy, K. K., Pandey, K., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110856 · Cited by 82 · see citing works
The cGAS-STING Pathway: Novel Perspectives in Liver Diseases
Xu, D., Tian, Y., Xia, Q., & Ke, B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.682736 · Cited by 82 · see citing works
Wang, F., Zhao, M., Chang, B., Zhou, Y., Wu, X., Ma, M., Liu, S., Cao, Y., Zheng, M., Dang, Y., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.03.034 · Cited by 78 · see citing works
Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING
Brown, H. E., Kwaku, G. N., Reardon, C. M., Khan, N. S., Zamith‐Miranda, D., Żarnowski, R., Tam, J. M., Bohaen, C. K., Richey, L. J., Mosallanejad, K., et al. (2024) · Nature Microbiology · doi:10.1038/s41564-023-01546-0 · Cited by 80 · see citing works
DNA Damage and Activation of cGAS/STING Pathway Induce Tumor Microenvironment Remodeling
Shen, R., Liu, D., Wang, X., Guo, Z., Sun, H., Song, Y., & Wang, D. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.828657 · Cited by 76 · see citing works
The CRL5–SPSB3 ubiquitin ligase targets nuclear cGAS for degradation
Xu, P., Liu, Y., Liu, C., Guey, B., Li, L., Mélénec, P., Ricci, J., & Ablasser, A. (2024) · Nature · doi:10.1038/s41586-024-07112-w · Cited by 77 · see citing works
cGAS–STING, an important signaling pathway in diseases and their therapy
Li, Q., Wu, P., Du, Q., Hanif, U., Hu, H., & Li, K. (2024) · MedComm · doi:10.1002/mco2.511 · Cited by 80 · see citing works
cGAS/STING cross-talks with cell cycle and potentiates cancer immunotherapy
Long, Z., Wang, J., Xu, J., Lei, X., & Liu, Q. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.01.044 · Cited by 73 · see citing works
Mitochondrial DNA signals driving immune responses: Why, How, Where?
Giordano, L., Ware, S. A., Lagranha, C. J., & Kaufman, B. A. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02042-0 · Cited by 77 · see citing works
cGAMP-activated cGAS–STING signaling: its bacterial origins and evolutionary adaptation by metazoans
Patel, D. J., Yu, Y., & Xie, W. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-00933-9 · Cited by 73 · see citing works
Nuclear cGAS: guard or prisoner?
Mann, C. C. D. O., & Hopfner, K. (2021) · The EMBO Journal · doi:10.15252/embj.2021108293 · Cited by 65 · see citing works
Nuclear cGAS: sequestration and beyond
Bai, J., & Liu, F. (2021) · Protein & Cell · doi:10.1007/s13238-021-00869-0 · Cited by 61 · see citing works
Torres-Odio, S., Lei, Y., Gispert, S., Maletzko, A., Key, J., Menissy, S. S., Wittig, I., Auburger, G. W. J., & West, A. P. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2001016 · Cited by 61 · see citing works
cGAS/STING signalling pathway in senescence and oncogenesis
Yu, L., & Liu, P. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.08.007 · Cited by 63 · see citing works
Opportunities and challenges of targeting cGAS–STING in cancer
Lu, C., Wang, W., & Fu, Y. (2026) · Nature reviews. Cancer · doi:10.1038/s41568-025-00894-9 · Cited by 70 · see citing works
STING Agonists and How to Reach Their Full Potential in Cancer Immunotherapy
Gehrcken, L., Deben, C., Smits, E., & Audenaerde, J. R. M. V. (2025) · Advanced Science · doi:10.1002/advs.202500296 · Cited by 64 · see citing works
ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress
Wardlaw, C. P., & Petrini, J. H. J. (2022) · Nature Communications · doi:10.1038/s41467-022-33535-y · Cited by 57 · see citing works
Nuclear and genome dynamics underlying DNA double-strand break repair
Chiolo, I., Altmeyer, M., Legube, G., & Mekhail, K. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00828-1 · Cited by 66 · see citing works
STING Signaling and Sterile Inflammation
Couillin, I., & Riteau, N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.753789 · Cited by 56 · see citing works
Targeting STING in cancer: Challenges and emerging opportunities
Zhao, K., Huang, J., Zhao, Y., Wang, S., Xu, J., & Yin, K. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188983 · Cited by 55 · see citing works
Micronucleus is not a potent inducer of the cGAS/STING pathway
Sato, Y., & Hayashi, M. (2024) · Life Science Alliance · doi:10.26508/lsa.202302424 · Cited by 56 · see citing works
Mitochondrial DNA in cell death and inflammation
Heilig, R., Lee, J., & Tait, S. W. G. (2023) · Biochemical Society Transactions · doi:10.1042/bst20221525 · Cited by 53 · see citing works
Regulation and inhibition of the DNA sensor cGAS
Hertzog, J., & Rehwinkel, J. (2020) · EMBO Reports · doi:10.15252/embr.202051345 · Cited by 51 · see citing works
Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth
Rao, K., Zhang, X., Luo, Y., Xia, Q., Jin, Y., & He, J. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115441 · Cited by 51 · see citing works
Tsuji, N., & Agbor-Enoh, S. T. (2021) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2021.03.007 · Cited by 51 · see citing works
Herpes Simplex Virus and Pattern Recognition Receptors: An Arms Race
Zhao, J., Qin, C., Liu, Y., Rao, Y., & Feng, P. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.613799 · Cited by 52 · see citing works
cGAS‐STING pathway: post‐translational modifications and functions in sterile inflammatory diseases
Hong, Z., Ma, T., Liu, X., & Wang, C. (2021) · FEBS Journal · doi:10.1111/febs.16137 · Cited by 50 · see citing works
Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response
Ma, H., Qian, W. P., Bambousková, M., Collins, P. L., Porter, S. I., Byrum, A. K., Zhang, R., Artyomov, M. N., Oltz, E. M., Mosammaparast, N., et al. (2020) · mBio · doi:10.1128/mbio.00136-20 · Cited by 50 · see citing works
Ribonucleotide incorporation into mitochondrial DNA drives inflammation
Bahat, A., Milenkovic, D., Cors, E., Barnett, M., Niftullayev, S., Katsalifis, A., Schwill, M., Kirschner, P., MacVicar, T., Giavalisco, P., et al. (2025) · Nature · doi:10.1038/s41586-025-09541-7 · Cited by 48 · see citing works
Control of innate immunity by the cGAS‐STING pathway
Mosallanejad, K., & Kagan, J. C. (2022) · Immunology and Cell Biology · doi:10.1111/imcb.12555 · Cited by 50 · see citing works
Song, B., Greco, T. M., Lum, K. K., Taber, C. E., & Cristea, I. M. (2020) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra120.001981 · Cited by 44 · see citing works
Role of Post-Translational Modifications of cGAS in Innate Immunity
Wu, Y., & Li, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217842 · Cited by 45 · see citing works
STING nuclear partners contribute to innate immune signaling responses
Dixon, C. R., Malik, P. R., Heras, J. I. D. L., Saiz-Ros, N., Alves, F. D. L., Tingey, M., Gaunt, E. R., Richardson, C. A., Kelly, D. A., Goldberg, M. W., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103055 · Cited by 45 · see citing works
Medicinal chemistry perspective on cGAS-STING signaling pathway with small molecule inhibitors
Tian, X., Xu, F., Zhu, Q., Feng, Z., Dai, W., Zhou, Y.-L., You, Q., & Xu, X. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114791 · Cited by 44 · see citing works
Molecular mechanisms of nonself nucleic acid recognition by the innate immune system
Mann, C. C. D. O., & Hornung, V. (2021) · European Journal of Immunology · doi:10.1002/eji.202049116 · Cited by 43 · see citing works
DNA-sensing pathways in health, autoinflammatory and autoimmune diseases
Dong, M., & Fitzgerald, K. A. (2024) · Nature Immunology · doi:10.1038/s41590-024-01966-y · Cited by 44 · see citing works
Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production
Zhang, K., Wang, S., Gou, H., Zhang, J., & Li, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.748485 · Cited by 42 · see citing works
cGAS-STING DNA-sensing in inflammatory bowel diseases
Dimitrov, G., Ryffel, B., Togbe, D., & Quesniaux, V. F. J. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.10.002 · Cited by 43 · see citing works
- Authors
- Volkman, H. E., Cambier, S., Gray, E. E., & Stetson, D. B.
- Affiliations
- University of Washington (US)
- Corresponding author
- Stetson, Daniel B
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2019-12-06
- Volume
- 8
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6927687
- OpenAlex
- W2994585472
- Cited by
- 303
- References
- 42
- Citations by year
- 2026: 38 · 2025: 42 · 2024: 55 · 2023: 36 · 2022: 37 · 2021: 59 · 2020: 36
- FWCI
- 13.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (AI084914)
- Jane Coffin Childs Memorial Fund for Medical Research
- Burroughs Wellcome Fund (1013540)
- Howard Hughes Medical Institute (55108572)
- Bill and Melinda Gates Foundation (OPP1156262)
- Cancer Research Institute (A84161)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- cGAS, innate immunity, double-stranded DNA sensing, self-DNA, autoreactivity, chromatin, cytosolic DNA sensing, constitutive activation, nucleic acid sensors
- MeSH terms
- Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Cell Nucleus, Cells, Cultured, Cytosol, DNA, DNA Damage, HeLa Cells, Humans, Mice, Inbred C57BL, Nuclear Proteins, Nucleotidyltransferases, Protein Binding, Cell Line, Tumor, DNA Cleavage
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